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Issue 3, 2016
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Palladium-catalyzed enolate arylation as a key C–C bond-forming reaction for the synthesis of isoquinolines

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Abstract

The palladium-catalyzed coupling of an enolate with an ortho-functionalized aryl halide (an α-arylation) furnishes a protected 1,5-dicarbonyl moiety that can be cyclized to an isoquinoline with a source of ammonia. This fully regioselective synthetic route tolerates a wide range of substituents, including those that give rise to the traditionally difficult to access electron-deficient isoquinoline skeletons. These two synthetic operations can be combined to give a three-component, one-pot isoquinoline synthesis. Alternatively, cyclization of the intermediates with hydroxylamine hydrochloride engenders direct access to isoquinoline N-oxides; and cyclization with methylamine, gives isoquinolinium salts. Significant diversity is available in the substituents at the C4 position in four-component, one-pot couplings, by either trapping the in situ intermediate after α-arylation with carbon or heteroatom-based electrophiles, or by performing an α,α-heterodiarylation to install aryl groups at this position. The α-arylation of nitrile and ester enolates gives access to 3-amino and 3-hydroxyisoquinolines and the α-arylation of tert-butyl cyanoacetate followed by electrophile trapping, decarboxylation and cyclization, C4-functionalized 3-aminoisoquinolines. An oxime directing group can be used to direct a C–H functionalization/bromination, which allows monofunctionalized rather than difunctionalized aryl precursors to be brought through this synthetic route.

Graphical abstract: Palladium-catalyzed enolate arylation as a key C–C bond-forming reaction for the synthesis of isoquinolines

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Publication details

The article was received on 11 Nov 2015, accepted on 20 Nov 2015 and first published on 03 Dec 2015


Article type: Paper
DOI: 10.1039/C5OB02320C
Citation: Org. Biomol. Chem., 2016,14, 1065-1090
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    Palladium-catalyzed enolate arylation as a key C–C bond-forming reaction for the synthesis of isoquinolines

    B. S. Pilgrim, A. E. Gatland, C. H. A. Esteves, C. T. McTernan, G. R. Jones, M. R. Tatton, P. A. Procopiou and T. J. Donohoe, Org. Biomol. Chem., 2016, 14, 1065
    DOI: 10.1039/C5OB02320C

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